JP7241916B2 - 7H-pyrrolo[2,3-D]pyrimidine JAK-inhibitors - Google Patents

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to US Provisional Patent Application No. 62/837,972, filed April 24, 2019, the contents of which are hereby incorporated by reference in their entirety.

The present disclosure provides 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidine-3- ii) polymorphs of acetonitrile, pharmaceutical compositions and processes for preparing the same and methods of using it, for example for the treatment of dermatological conditions.

WO 2009/114512 discloses the compound 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclo Discloses the preparation of certain JAK inhibitors, including propylsulfonyl)azetidin-3-yl)acetonitrile (Example 80), as the trifluoroacetate salt (Example 2) and as the phosphate salt (Example 81). there is

2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclo There is a need for propylsulfonyl)azetidin-3-yl)acetonitrile and methods for its preparation and purification that can be used effectively and reproducibly on a large scale for industrial manufacturing. In particular, crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)- which can be used effectively, safely and reproducibly There is a need for 1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile and methods for its preparation and purification that can be used effectively and reproducibly on a large scale for industrial manufacturing. In particular, substantially polymorphically pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- which can be used effectively, safely and reproducibly 1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile and methods for preparation and purification that can be used effectively and reproducibly on a large scale for industrial production and are required.

In certain embodiments, the present disclosure provides substantially polymorphically pure crystalline Form I 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H- Pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile and processes for making same are provided. In certain embodiments, the present disclosure provides substantially polymorphically pure crystalline Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H- Pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile and processes for making same are provided. In certain embodiments, the present disclosure provides substantially polymorphically pure Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole -1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile and processes for making same.

In certain embodiments, the present disclosure provides substantially polymorphically pure Form I 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole Pharmaceutical compositions are provided comprising -1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile and a pharmaceutically acceptable excipient. In certain embodiments, the present disclosure provides substantially polymorphically pure Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole Pharmaceutical compositions are provided comprising -1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile and a pharmaceutically acceptable excipient. In certain embodiments, the present disclosure provides substantially polymorphically pure Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole Pharmaceutical compositions are provided comprising -1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile and a pharmaceutically acceptable excipient.

In certain embodiments, the present disclosure provides a method of treating a dermatological condition comprising administering to a non-human mammal in need thereof substantially polymorphically pure form I 2-(3-(). administering an effective amount of 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile to provide a method comprising: In certain embodiments, the present disclosure provides a method of treating a dermatological condition comprising administering substantially polymorphically pure Form II 2-(3-() to a non-human mammal in need thereof. administering an effective amount of 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile to provide a method comprising: In certain embodiments, the present disclosure provides a method of treating a dermatological condition comprising administering substantially polymorphically pure Form III 2-(3-() to a non-human mammal in need thereof. administering an effective amount of 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile to provide a method comprising:

In certain embodiments, the present disclosure provides 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1(cyclopropylsulfonyl ) azetidin-3-yl) acetonitrile and intermediates thereof.

The present disclosure provides the compound 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidine- 3-yl) acetonitrile, polymorphs thereof identified herein as Form I, Form II and Form III, and pharmaceutical compositions thereof, and methods of using the polymorphs, for example, for the treatment of dermatological conditions; It also relates to methods of making polymorphs and methods of making the compounds and intermediates thereof.

1. DEFINITIONS Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present specification, including definitions, will control. Although preferred methods and materials are described below, methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not limiting.

The terms "comprise", "include", "having", "have", "can", "contain" and variations thereof when used herein have the further effect or open-ended transitional phrases, terms or words that do not preclude structural possibilities. The singular forms of "a", "an" and "the" include plural references unless the content clearly dictates otherwise. This disclosure “comprising,” “consisting of,” and “consisting essentially of” any embodiment or element set forth herein, whether explicitly indicated or not, and other Embodiments are also contemplated.

The term “about,” when used in connection with a measurable numerical variable, means the indicated value of the variable and within experimental error of the indicated value or within ±10 percent of the indicated value, whichever is wider. refers to all values of variables that are

The term "acceptable excipient" refers to those commonly used in preparing veterinary and pharmaceutical compositions and should be pure and non-toxic in the amounts used. These are generally solid, semi-solid or liquid substances which can be the vehicle or medium for the active ingredient in aggregates. Some examples of acceptable excipients are found in Remington's Pharmaceutical Sciences and the Handbook of Pharmaceutical Excipients and include diluents, vehicles, carriers, ointment bases, binders, disintegrants, lubricants, Glidants, sweeteners, flavoring agents, gel bases, sustained release matrices, stabilizers, preservatives, solvents, suspending agents, buffers, emulsifiers, dyes, propellants, coating agents and the like.

The term "aromatic solvent" refers to benzene optionally substituted with one or two substituents selected from the group consisting of methyl, chloro, bromo, cyano, nitro, aceto. The term "aromatic solvent" specifically includes nitrobenzene, chlorobenzene, toluene, xylene and acteophenone.

The term "C _1-5 alcohol" refers to straight or branched alkanols having 1 to 5 carbon atoms, such as methanol, ethanol, n-propanol, isopropanol, 1-butanol, ethylene glycol, 1,3-propanediol. etc.

The term "C ₁ -C ₄ alkyl" refers to straight or branched alkyl chains having 1 to 4 carbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl and the like.

The term "C _2-8 alkyl ether" means a linear, branched or cyclic alkyl ether having a total of 2 to 8 carbon atoms, such as dimethyl ether, diethyl ether, methyl t-butyl ether, THF, 2-methylTHF, It refers to dioxane, etc.

The term "C _3-8 alkyl acetate" refers to linear or branched alkyl esters of acetic acid having a total of 3 to 8 carbons, such as methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate and the like.

The term "C _2-5 alkyl cyanide" refers to linear or branched alkyl cyanides having a total of 2 to 5 carbon atoms, such as acetonitrile, propionitrile and butyronitrile.

The term "C _3-9 alkyl ketone" refers to a linear, branched or cyclic alkyl group having an oxo group and having a total of 3 to 9 carbon atoms, such as acetone, methyl ethyl ketone and cyclohexanone.

The term "C _5-8 hydrocarbon" refers to straight chain, branched or cyclic saturated alkyl hydrocarbons such as pentane, hexane, heptane, octane, cyclopentane, cyclohexane, methylcyclohexane and the like.

The term “5- to 6-membered heterocyclic ring” refers to a 5- to 6-membered monocyclic saturated ring containing an oxygen atom to which R ₁ and R ₂ are attached and a boron to which these oxygen atoms are attached.

Terms such as "crystallize", "crystallizing", "crystallization" refer to a slurry process that does not include complete dissolution followed by precipitation and complete dissolution. Slurry processes include those involving complete dissolution followed by precipitation followed by continuation of the crystallization process.

The term "dermatological condition" includes psoriasis (e.g., psoriasis vulgaris), atopic dermatitis, rash, skin irritation, skin sensitization (e.g., contact dermatitis or allergic contact dermatitis), allergic Includes skin disorders such as itching and allergic reactions, including itching associated with dermatitis.

The term "effective amount" refers to that amount or dose of a compound of the invention, or a pharmaceutically acceptable salt thereof, that provides the desired effect in a patient under diagnosis or treatment upon single or multiple administrations to the patient. Point. An effective amount can be readily determined by an attending diagnostician such as one skilled in the art by the use of known techniques and by observing results obtained under analogous circumstances. the species of the patient or non-human mammal; its size, age and general health; the specific disease or disorder involved; the degree of involvement or severity of the disease or disorder; specific compound administered; mode of administration; bioavailability characteristics of the preparation administered; dosing regimen selected; use of concomitant medications; Factors are considered by the attending diagnostician.

The terms "patient", "subject" and "non-human mammal" refer to warm-blooded animals such as dogs, cats, mice, rats, guinea pigs, rabbits, cows, horses, sheep, goats and pigs. Particular non-human mammals are pet or companion animals such as dogs and cats and also mice, guinea pigs and rabbits. Preferred non-human mammals are dogs and cats. Preferably, the non-human mammal is a canine. A particularly preferred non-human mammal is a dog.

The term "salt" refers to salts of veterinary or pharmaceutically acceptable organic or inorganic acids and bases. Such salts are well known in the art and include those described in Journal of Pharmaceutical Science, 66, 2-19 (1977). One example is hydrochloride. This term, as used herein, specifically excludes trifluoroacetates and phosphates.

The term "substantially polymorphically pure" refers to a polymorphic purity of greater than 90%, preferably greater than 97%, more preferably greater than 99% and even more preferably greater than 99.5%.

The terms "treating" or "treating" refer to slowing, slowing, halting or reversing the progression or severity of an existing symptom or disorder.

The term "water activity" is equal to p/p ^* , where p is the water vapor partial pressure of water in solution and p ^* is the water vapor partial pressure of pure water at the same temperature. .

For reference to numerical ranges herein, each numerical value therebetween with comparable degrees of precision is expressly contemplated. For example, for the range 92-97, in addition to 92 and 97, numbers 93, 94, 95 and 96 are contemplated, and numbers within the range 92.1, 92.2, 92.3, 92.4, 92 .5, 92.6, etc. to 97.0 are expressly contemplated.

2. Compounds The compound of the present invention is 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidine -3-yl)acetonitrile crystalline forms I, II and III. 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile Crystalline forms are desirable for efficiency and reproducibility of production of pharmaceutical formulations and for providing pharmaceutical compositions with adequate stability.

2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile is , 2-[1-cyclopropylsulfonyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]azetidin-3-yl]acetonitrile and 2-(1 -cyclopropylsulfonyl-3-pyrazol-1-yl-(4-(7H-pyrrolo[2,3-d]pyrimidineazetidin-3-yl)acetonitrile, for clarity are compounds of formula (I) below.

In a preferred embodiment, the compounds of the invention are in the crystalline form I 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H as described herein -pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile. Crystal Form I 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl ) Acetonitrile is an anhydride.

In another preferred embodiment, the compounds of the invention are in crystalline form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl) as described herein -1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile. Crystal Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl ) Acetonitrile is also an anhydride.

In another preferred embodiment, the compounds of the invention are in crystalline form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl) as described herein -1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile. Crystal Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl ) Acetonitrile is in hydrated form.

2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile Forms I, II and III, as well as other polymorphic forms, can be characterized by X-ray diffraction. Peaks were measured using a powder diffractometer with a copper line source, a primary beam monochromator and a position sensitive detector. A 1° divergence slit was used to collimate the incident beam. The source was operated at 40 kV and 40 mA. X-ray powder diffraction data were collected from 2.5° to 50° using a step width of 0.02° and a step time of 37 seconds. Instead, peaks were measured using a powder diffractometer with a copper line source, a primary beam monochromator and a position sensitive detector. A 1° divergence slit was used to collimate the incident beam. The source was operated at 40 kV and 40 mA. X-ray powder diffraction data were collected from 1.5° to 50° using a step width of 0.02° and a step time of 12 seconds.

It is recognized that the relative intensities of X-ray diffraction peaks can depend on other factors such as preferred orientation and grain size. The characteristic peak position of the polymorph remains unchanged, although the peak intensity may change when preferred orientation and/or particle size effects are present. See, eg, The United States Pharmacopoeia #24, National Formulary #19, pages 1843-1844, 2000. Thus Form I, or Form II, or Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-( Samples of cyclopropylsulfonyl)azetidin-3-yl)acetonitrile may require processing to mitigate such factors, such as grinding the sample in an agate mortar and pestle or other means. Differences in the relative intensities of the diffraction peaks are either Form I, or Form II, or Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole-1 -yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile is understood not to exclude the pattern obtained.

Furthermore, it is well known in the art of crystallography that the angular positions of the peaks may vary slightly for any particular crystal type. For example, peak positions may shift due to sample displacement or variations in temperature or relative humidity at which the sample is analyzed. In the present case, the ±0.2° peak position variability in 2-theta does not preclude unambiguous identification of the crystalline forms of the present disclosure and takes these possible variations into account.

Form I, II or III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidine- 3-yl)acetonitrile is also characterized by differential scanning calorimetry. DSC is a closed (sealed) gold crucible or aluminum pan with a pinhole; sample filling (3-10 min) under ambient conditions or _N2 flow; minutes.

Form I
Crystal Form I 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl ) acetonitrile was found to have the following peaks at degrees two theta (°2θ) with (relative intensity, I ₀ /I ₁₀₀ % greater than about 10% of maximum peak): 12.72° (43. 1%), 14.04° (61.3%), 17.56° (20.8%), 20.33° (87.4%), 24.50° (100%) and 25.83° (94.9%) (±0.2°2θ).

The present disclosure provides an X-ray powder containing peaks at 12.72°, 14.04°, 17.56°, 20.33°, 24.50° or 25.83° two-theta (±0.2° two-theta) Substantially polymorphically pure form I 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole-1- characterized by a diffraction pattern yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile. More specifically, the present disclosure includes peaks at 12.72° and 24.50° (±0.2° 2-theta) or 20.33° and 24.50° (±0.2° 2-theta) or substantially polymorphically pure characterized by an X-ray powder diffraction pattern comprising peaks at 12.72° and 20.33° (±0.2° 2-theta) Form I 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl ) to provide acetonitrile.

As used herein, "Form I 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1- (Cyclopropylsulfonyl)azetidin-3-yl)acetonitrile" means "substantially polymorphically pure Form I 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile”.

Form II
Crystal Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl ) acetonitrile was found to have the following peaks at degrees two theta (°2θ) with (relative intensity, I ₀ /I ₁₀₀ % greater than about 10% of maximum peak): 5.34° (16. 2%); 10.68° (26.2%); 14.26° (20.8%); 16.06° (13.5%); 16.39° (17.9%); 48° (18.6%); 18.26° (19.5%); 18.65° (43.4%); 19.03° (100.0%); 21.05° (10.2 %); 21.15° (9.9%); 21.45° (9.0%); 21.76° (20.5%); 22.45° (9.6%); 22.68 ° (22.5%); 23.23° (11.1%); 23.72° (12.3%); 24.90° (11.7%); 25.08° (9.2%) ); 26.75° (30.7%); and 31.18° (10.1%); (±0.2° 2-theta).

5.34°, 10.68°, 14.26°, 16.06°, 16.39°, 16.48°, 18.26°, 18.65°, 19.03°, 21 substantially polymorphically pure, characterized by an X-ray powder diffraction pattern containing peaks at .05°, 21.76°, 22.68° or 26.75° (±0.2° 2-theta) Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl) Provide acetonitrile. More specifically, the present disclosure includes peaks at 18.65° and 10.68° (±0.2° 2-theta) or 18.65° and 21.76° (±0.1° 2-theta), or peaks at 18.65° and 22.68° (±0.1° 2-theta), or peaks at 26.75° and 21.76° (±0.2° Substantially polymorphically pure Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4) characterized by an X-ray powder diffraction pattern containing a peak at 2θ) -yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile.

As used herein, "Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1- (Cyclopropylsulfonyl)azetidin-3-yl)acetonitrile" means "substantially polymorphically pure Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile”.

Form III
Crystal Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl ) acetonitrile was found to have the following peaks at degrees 2 theta (°2θ) with (relative intensity, I ₀ /I ₁₀₀ % greater than about 10% of maximum peak): 11.08° (62. 12.32° (15.9%); 13.28° (13.7%); 14.06° (15.3%); 14.73° (32.8%); 86° (16.9%); 18.06° (46.4%); 18.27° (18.1%); 18.51° (35.2%); 18.91° (10.9 %); 20.36° (15.8%); 21.48° (12.7%); 22.24° (26.9%); 22.69° (100%); 24.76° (18.8%); 25.48° (55.4%); 25.97° (12.6%); 26.70° (12.5%); and 28.04° (12.8%); (±0.2°2θ)°.

11.08°, 14.73°, 18.06°, 18.27°, 18.51°, 22.24°, 22.69°, 24.76°, 25.48° or 28° Substantially polymorphically pure Form III 2-(3-(4-(7H-pyrrolo[ 2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile. In particular, the present disclosure includes peaks at 11.08° and 22.69°; (±0.2° 2-theta); or peaks at 22.69° and 25.48° (±0.2° 2θ), or peaks at 11.08° and 18.06° (±0.2° 2θ) or characterized by an X-ray powder diffraction pattern comprising peaks at 11.08° and 25.48° (±0.2° 2-theta) 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile offer.

As used herein, "Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1- The term (cyclopropylsulfonyl)azetidin-3-yl)acetonitrile" refers to "substantially polymorphically pure Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile”.

Those skilled in the art will recognize that compounds can exist as tautomers. All tautomeric forms of the compounds of the invention are contemplated within the scope of the present disclosure.

The compounds of the present invention also include all isotopic variations in which at least one atom of the predominant atomic mass is replaced by an atom having the same atomic number but an atomic mass different from the predominant atomic mass. Use of isotopic variations (eg, deuterium, ² H) may allow greater metabolic stability. Additionally, certain isotopic variations of the compounds of the present invention may incorporate radioactive isotopes (eg, tritium, ³ H or ¹⁴ C), which may be useful in drug and/or substrate tissue distribution studies. Substitution with positron emitting isotopes, such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N, can be useful in Positron Emission Tomography (PET) studies.

3. Process for Making Crystal Forms Form I Process Crystal Form I 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1 -(Cyclopropylsulfonyl)azetidin-3-yl)acetonitrile can be prepared by crystallization under controlled conditions. The present disclosure provides substantially polymorphically pure crystalline Form I 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl) Also provided is a process for making 1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile comprising crystallization from a mixture of acetone and heptane as antisolvents. In a preferred embodiment, Form I 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidine -3-yl)acetonitrile can also be obtained by dehydration of a Form III sample, such as by heating at a temperature of about 40°C to about 80°C, typically under vacuum.

Form II Process Crystalline Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidine- 3-yl)acetonitriles may be prepared by crystallization under controlled conditions by crystallization from a solvent or mixture of solvents. The present disclosure provides substantially polymorphically pure crystalline Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl) - A process for making 1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile comprising crystallization from a solvent or mixture of solvents further containing water and having a water activity of less than 0.7 It also provides a process that includes In practice, suitable solvents are C _1-5 alcohols, C _2-8 alkyl ethers, C _2-8 alkyl acetates, C _2-5 alkyl cyanides, C _{3-5 9} selected from the group consisting of alkyl ketones and aromatic solvents.

In a preferred embodiment, the present disclosure provides substantially polymorphically pure crystalline Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole Process for making 1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile, the solvent or mixture of solvents further containing water and having a water activity of less than 0.5 A process comprising crystallization from is also provided.

The use of antisolvents can be advantageous. As used in this context, "antisolvent" is 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl) -1-(Cyclopropylsulfonyl)azetidin-3-yl)acetonitrile refers to the solvent with significantly lower solubility in the chosen solvent. Preferably, if an antisolvent is used, it is miscible with the chosen solvent. While antisolvents may be used, care must be taken that the antisolvent chosen does not increase water activity beyond the desired level.

substantially polymorphically pure crystalline form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-( It is understood that water activity to provide cyclopropylsulfonyl)azetidin-3-yl)acetonitrile is temperature dependent. Higher temperatures in the final state of crystallization can withstand higher water activity. Thus, a water activity of about 0.7 is effective at temperatures of final state of crystallization above about 40°C.

Since recovery is greater at lower temperatures, in preferred embodiments, the present disclosure provides substantially polymorphically pure crystalline Form II 2-(3-(4-(7H-pyrrolo[2,3-d). ] pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile having a water activity of less than 0.5 Also provided are processes involving crystallization from a solvent or mixture of solvents. Generally, a water activity of about 0.5 is effective at temperatures of crystallization end conditions of less than about 25°C.

Preferred solvents are selected from the group consisting of C _1-5 alcohols and C _2-5 alkyl cyanides each having a water activity of less than about 0.7. Even more preferred solvents are selected from the group consisting of C _1-5 alcohols and C _2-5 alkyl cyanides each having a water activity of less than about 0.5.

In certain embodiments, the present disclosure provides substantially polymorphically pure crystalline Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H- A process for making pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile, further comprising water and crystallizing from acetonitrile having a water activity of less than 0.7. It also provides a process that includes

In another particular embodiment, the present disclosure provides substantially polymorphically pure crystalline Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- A process for making 1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile comprising crystallization from acetonitrile further comprising water having a water activity of less than 0.5 It also provides a process that includes

The present disclosure provides substantially polymorphically pure crystalline Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl) Also provided is a process of making -1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile comprising crystallization from acetonitrile further comprising water. Care must be taken to avoid the formation of undesirable hydrated crystal forms. Therefore, a preferred embodiment for crystallization from acetonitrile that further comprises water utilizes a v/v ratio of 92-97 acetonitrile to 8-3 water; Crystallized from acetonitrile further containing water in a v/v ratio of water of 3. It was found that the use of 96:4 (v/v) acetonitrile/water actually has the most favorable volumetric efficiency at temperatures below about 20°C.

Thus, substantially polymorphically pure crystalline Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1 An even more preferred process for making -(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile is to crystallize from acetonitrile further comprising water at a v/v ratio of about 96 acetonitrile to about 4 water. include.

Optionally, the crystallization is Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclo It can be seeded with propylsulfonyl)azetidin-3-yl)acetonitrile.

Precipitation from solution and crystallization by slurrying techniques are contemplated within the scope of the process. If crystallization involves complete dissolution, slow cooling at a rate of 0.2° C./min to 0.02° C./min is preferred. Crystallization to obtain Form II does not require complete dissolution. A slurry process may be used. Slurries can be formed by processing without complete dissolution, or by complete dissolution followed by processing after initial precipitation. In slurry processes, the volume should be sufficient to provide a free-flowing slurry. The volume of solvent is not critical, but should be kept to a minimum for convenience. The water activity of the solvent used must take into account water, including water that can be released from the hydrated starting material. Optionally, the slurry crystallization process forms Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1- (Cyclopropylsulfonyl)azetidin-3-yl)acetonitrile can be used for seeding.

In one embodiment, 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidine-3 -yl)acetonitrile-containing non-Form II is crystallized from the slurry at a temperature of about 50° C. or above and optional cooling to recover the final product. In another embodiment, non-Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl )azetidin-3-yl)acetonitrile is crystallized by slurry from a solvent at a temperature around room temperature. Optionally, the crystallization is Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclo It can be seeded with propylsulfonyl)azetidin-3-yl)acetonitrile. Such a slurry process generally takes 2-14 days.

Form III Process Crystalline Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidine- 3-yl)acetonitriles may be prepared by crystallization under controlled conditions by crystallization from a solvent or mixture of solvents. The present disclosure provides substantially polymorphically pure crystalline Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl) - A process for making 1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile comprising crystallization from a solvent or mixture of solvents further containing water and having a water activity greater than 0.9 It also provides a process that includes In practice, suitable solvents consist of water, C _1-5 alcohols, C _2-8 alkyl acetates, C _2-5 alkyl cyanides and C _3-9 alkyl ketones, each having a water activity greater than about 0.9. selected from the group.

The use of antisolvents can be advantageous. As used in this context, "antisolvent" is 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl) -1-(Cyclopropylsulfonyl)azetidin-3-yl)acetonitrile refers to a solvent in which it is significantly less soluble compared to the chosen solvent. Preferably, if an antisolvent is used, it is miscible with the chosen solvent.

While the antisolvent is used, care must be taken that the antisolvent chosen does not reduce the water activity below the desired level.

Preferred solvents are selected from the group consisting of C _1-5 alcohols having a water activity greater than about 0.9.

Crystallization from solution and slurry techniques are contemplated within the scope of this process. If crystallization involves complete dissolution, slow cooling at a rate of 0.2° C./min to 0.02° C./min is preferred. Crystallization to obtain Form III does not require complete dissolution. A slurry process may be used. Slurries can be formed by processing without complete dissolution, or by complete dissolution followed by processing after initial precipitation. In slurry processes, the volume should be sufficient to provide a free-flowing slurry. The volume of solvent is not critical, but should be kept to a minimum for convenience. Optionally, the slurry crystallization process forms Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-( It can be seeded with cyclopropylsulfonyl)azetidin-3-yl)acetonitrile.

In one embodiment, 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidine-3 -yl)acetonitrile-containing non-form III is crystallized by slurry from a solvent having a water activity greater than 0.9 at temperatures around room temperature. Optionally, crystallization is performed in Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclo It can be seeded with propylsulfonyl)azetidin-3-yl)acetonitrile. Such a slurry process generally takes 2-10 days.

Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl) is preferably Care must be taken when drying -1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile.

4. Methods of Synthesis The present disclosure provides 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1- as shown in Scheme A. A process for making (cyclopropylsulfonyl)azetidin-3-yl)acetonitrile is provided.

In Scheme A, Step 1, a compound of formula (1) is reacted with a compound of formula (2) in the presence of a suitable catalyst to give a compound of formula (3). Compounds of formula (1) are those in which X is selected from the group consisting of tosylate, triflate, chloro, bromo and iodo and Pg is a protecting group. Indeed, compounds of formula (1) where X is bromo or chloro are preferred, with chloro being even more preferred. A variety of protecting groups are suitable. Selection of suitable protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups is described, for example, in T.W. W. Greene andP. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed. , Wiley & Sons, Inc. , New York (1999). For example, t-BOC, 2-(trimethylsilyl)ethoxymethyl and N-pivaloyloxymethyl are useful, to name just a few. In fact, the t-BOC group is preferred. Compounds of formula (2) are those wherein R ₁ and R ₂ are independently selected from the group consisting of hydrogen and C _1-6 alkyl; or R ₁ and R ₂ are the oxygen atom to which they are linked and together with the boron atom form a 5-6 membered heterocyclic ring optionally substituted with 1, 2, 3 or 4 C _1-4 alkyl groups. As will be appreciated by those skilled in the art, the reaction shown in Step 1 is the well-known Suzuki reaction. Various suitable catalysts are available. Both nickel and palladium catalysts are useful, but palladium catalysts are preferred. Many suitable palladium(0) and palladium(II) catalysts are known in the art. For example, tetrakis(triphenylphosphine)palladium(0), tetrakis(triphenylphosphine)palladium(II) chloride, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and dichloromethane[1,1′- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1:1).

This reaction is generally carried out in solvents, including a wide variety of organic solvents. Solvents may contain water. For example, suitable solvents include 1,4-dioxane, THF, 1-butanol, 1,2-dimethoxyethane (DME), 2-propanol, toluene or ethanol or combinations thereof. A typical palladium catalyst is used in amounts of about 0.01 to about 0.1 equivalents.

This reaction is carried out in the presence of a base. Both organic and inorganic bases can be used, for example bases such as alkali metal carbonates and bicarbonates and cesium carbonate. The reaction is generally carried out at a temperature of about 40°C to about 100°C and generally takes 1-18 hours.

5. Pharmaceutical compositions -3-yl)acetonitrile or a salt thereof and an acceptable excipient. In preferred embodiments, the present disclosure provides crystalline Form I, or Form II, or Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole- Pharmaceutical compositions comprising 1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile and acceptable excipients are provided. In another preferred embodiment, the present disclosure provides crystalline Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1 A pharmaceutical composition comprising -(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile and at least one acceptable excipient is provided. In another preferred embodiment, the present disclosure provides substantially polymorphically pure crystalline Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H -pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile and at least one acceptable excipient.

The compounds of the invention may be administered alone or in the form of compositions. In practice, the compounds of the invention are usually administered in the form of a composition, i.e. as an admixture with at least one acceptable excipient. The proportions and nature of any acceptable excipients are determined by the properties of the compound of the invention selected, the route of administration chosen and standard techniques such as those in the veterinary and pharmaceutical arts.

In effecting treatment of a subject in need of such treatment, the compounds of the invention may be administered in any form and route that makes the compounds bioavailable.

The compounds of the invention can be administered by a variety of routes including orally, particularly by tablets and capsules. The compounds of this invention can be administered by parenteral routes, especially by inhalation, subcutaneously, intramuscularly, intravenously, intraarterially, transdermally, intranasally, rectally, vaginally, ocularly, topically. , sublingually and buccally, intraperitoneally, intrafatly, intrathecally and via local delivery, eg by catheter or stent.

Those skilled in the art can readily select the appropriate form and route of administration depending on the particular characteristics of the compound selected, the disorder or condition to be treated, the stage of the disorder or condition and other relevant circumstances. Pharmaceutical compositions of the present invention are in the form of, for example, tablets, capsules, cachets, papers, lozenges, wafers, elixirs, ointments, transdermal patches, aerosols, inhalants, suppositories, drenches, solutions and suspensions. can be administered to the patient at

In one embodiment, the composition is adapted for oral administration, such as tablets or capsules, or a liquid formulation, such as a solution or suspension, adapted for oral administration. In one embodiment, the composition is adapted for oral administration, such as a chewable formulation, and is adapted for oral administration. In yet another embodiment, the composition is a liquid or semi-solid formulation adapted for parenteral administration, such as a solution or suspension or paste.

The compositions of the present disclosure are prepared in a manner well known in the veterinary and pharmaceutical arts and contain at least one of the compounds of the present invention as an active ingredient. The amount of a compound of the disclosure may vary depending on its particular form and may conveniently be from 1% to about 50% by weight of unit dosage form. The pharmaceutical compositions are preferably formulated in unit dosage form, each dose generally containing from about 0.25 mg to about 10 mg of a compound of the invention. One or more unit dosage forms can be selected to affect the treatment dosage.

6. Methods of Use The present disclosure provides a method of treating a dermatological condition comprising administering to a non-human mammal in need thereof an effective amount of a compound of the invention.

In certain embodiments, the present disclosure relates to dermatological conditions [e.g., skin disorders, e.g., psoriasis (e.g., psoriasis vulgaris), atopic dermatitis, rashes, skin irritation, skin sensitization (e.g., contact dermatitis). or allergic contact dermatitis), itching and allergic reactions, including itching associated with allergic dermatitis], wherein a non-human mammal in need thereof comprises: Effective amount of (4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile or a salt thereof A method is provided comprising administering A preferred non-human mammal is a dog. In certain embodiments, the dog is at least 9 months old or at least 12 months old.

In preferred embodiments, the present disclosure is directed to dermatological conditions [e.g., skin disorders such as psoriasis (e.g., psoriasis vulgaris), atopic dermatitis, rashes, skin irritation, skin sensitization (e.g., contact dermatitis or allergic contact dermatitis, itching and allergic reactions, including itching associated with allergic dermatitis], comprising administering to a non-human mammal in need thereof crystalline Form I, or Form II, or Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidine-3 -yl) acetonitrile. A preferred non-human mammal is a dog. In certain embodiments, the dog is at least 9 months old or at least 12 months old.

In particularly preferred embodiments, the present disclosure is directed to dermatological conditions [e.g., skin disorders such as psoriasis (e.g., psoriasis vulgaris), atopic dermatitis, rashes, skin irritation, skin sensitization (e.g., contact dermatitis). or allergic contact dermatitis), itching and allergic reactions, including itching associated with allergic dermatitis], comprising administering to a non-human mammal in need thereof crystalline Form II 2 Effectiveness of -(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile A method is provided comprising administering an amount. A preferred non-human mammal is a dog. In certain embodiments, the dog is at least 9 months old or at least 12 months old.

In even more particularly preferred embodiments, the present disclosure is directed to dermatological conditions [e.g., skin disorders such as psoriasis (e.g., psoriasis vulgaris), atopic dermatitis, rashes, skin irritation, skin sensitization (e.g., contact skin), inflammation or allergic contact dermatitis), pruritus and allergic reactions, including pruritus associated with allergic dermatitis, etc., in a non-human mammal in need thereof, substantially Polymorphically pure crystalline Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl) a) azetidin-3-yl) acetonitrile. A preferred non-human mammal is a dog. In certain embodiments, the dog is at least 9 months old or at least 12 months old.

In certain embodiments, the present disclosure provides a method of treating atopic dermatitis comprising administering to a non-human mammal in need thereof 2-(3-(4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile or a salt thereof. In a preferred embodiment, the present disclosure provides a method of treating atopic dermatitis comprising administering crystalline Form I, or Form II, or Form III 2-(3-(4) to a non-human mammal in need thereof. - (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile Provide a method that includes In a particularly preferred embodiment, the present disclosure provides a method of treating atopic dermatitis comprising administering to a non-human mammal in need thereof crystalline Form II 2-(3-(4-(7H-pyrrolo[2). ,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile. In a more particularly preferred embodiment, the present disclosure provides a method of treating atopic dermatitis comprising administering substantially polymorphically pure crystalline Form II 2-(3) to a non-human mammal in need thereof. - administering an effective amount of (4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile providing a method comprising: A preferred non-human mammal is a dog. In certain embodiments, the dog is at least 9 months old or at least 12 months old.

In certain embodiments, the present disclosure provides a method of treating pruritus associated with allergic dermatitis comprising administering 2-(3-(4-(7H-pyrrolo) to a non-human mammal in need thereof. [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile or a salt thereof. I will provide a. In a preferred embodiment, the present disclosure provides a method of treating pruritus associated with allergic dermatitis comprising administering to a non-human mammal in need thereof crystalline Form I, or Form II, or Form III 2- Effective amount of (3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile A method is provided comprising administering In a particularly preferred embodiment, the present disclosure provides a method of treating pruritus associated with allergic dermatitis comprising administering crystalline Form II 2-(3-(4-() to a non-human mammal in need thereof. A method comprising administering an effective amount of 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile I will provide a. In a more particularly preferred embodiment, the present disclosure provides a method of treating pruritus associated with allergic dermatitis comprising administering to a non-human mammal in need thereof a substantially polymorphically pure crystalline form. II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile A method is provided comprising administering an effective amount of A preferred non-human mammal is a dog. In certain embodiments, the dog is at least 9 months old or at least 12 months old.

Effective amounts can range, for example, from 0.5 mg to 100 mg. Specific amounts can be determined by those skilled in the art. Although these dosages are based on patients having masses from about 0.5 kg to about 80 kg, the diagnostician can determine appropriate doses for subjects whose masses fall outside this weight range. Effective amounts can range, for example, from 0.1 mg to 1.2 mg/kg patient, 0.3 mg to 1.0 mg/kg patient, or 0.4 mg to 0.6 mg/kg patient. Dosing regimens can be, for example, daily, twice daily, weekly or monthly administration.

In certain embodiments, the present disclosure relates to dermatological conditions in non-human mammals [e.g., skin disorders such as psoriasis (e.g., psoriasis vulgaris), atopic dermatitis, rashes, skin irritation, skin sensitization (e.g., 2-(3-(4-( 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile or a salt thereof is provided. A preferred non-human mammal is a dog. In certain embodiments, the dog is at least 9 months old or at least 12 months old.

In preferred embodiments, the present disclosure is directed to dermatological conditions [e.g., skin disorders such as psoriasis (e.g., psoriasis vulgaris), atopic dermatitis, rashes, skin irritation, skin sensitization (e.g. contact dermatitis or allergic contact dermatitis), itching and allergic reactions, including itching associated with allergic dermatitis, etc.] III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile I will provide a. A preferred non-human mammal is a dog. In certain embodiments, the dog is at least 9 months old or at least 12 months old.

In particularly preferred embodiments, the present disclosure is directed to dermatological conditions [e.g., skin disorders such as psoriasis (e.g., psoriasis vulgaris), atopic dermatitis, rashes, skin irritation, skin sensitization (e.g., crystalline form II 2-(3-( 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile is provided. A preferred non-human mammal is a dog. In certain embodiments, the dog is at least 9 months old or at least 12 months old.

In a further particularly preferred embodiment, the present disclosure is directed to dermatological conditions [e.g., skin disorders such as psoriasis (e.g., psoriasis vulgaris), atopic dermatitis, rashes, skin irritation, skin sensitization ( contact dermatitis or allergic contact dermatitis), pruritus, including pruritus associated with allergic dermatitis, and allergic reactions, etc.]. crystalline form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidine-3- yl) providing acetonitrile. A preferred non-human mammal is a dog. In certain embodiments, the dog is at least 9 months old or at least 12 months old.

In certain embodiments, the present disclosure provides 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4) for use in treating atopic dermatitis in a non-human mammal. -yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile or a salt thereof. In a preferred embodiment, the present disclosure provides crystalline Form I, or Form II, or Form III 2-(3-(4-(7H-pyrrolo [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile. In a particularly preferred embodiment, the present disclosure provides crystalline Form II 2-(3-(4-(7H-pyrrolo[2,3-d]) for use in treating atopic dermatitis in a non-human mammal. pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile. In a more particularly preferred embodiment, the present disclosure provides substantially polymorphically pure crystalline Form II 2-(3-(4-() for use in treating atopic dermatitis in a non-human mammal. 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile. A preferred non-human mammal is a dog. In certain embodiments, the dog is at least 9 months old or at least 12 months old.

In certain embodiments, the present disclosure provides 2-(3-(4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile or a salt thereof. In a preferred embodiment, the present disclosure provides crystalline Form I, or Form II, or Form III 2-(3-(4) for use in treating pruritus associated with allergic dermatitis in a non-human mammal. -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile. In a particularly preferred embodiment, the present disclosure provides crystalline Form II 2-(3-(4-(7H-pyrrolo[2) for use in the treatment of pruritus associated with allergic dermatitis in non-human mammals. ,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile. In a more particularly preferred embodiment, the present disclosure provides substantially polymorphically pure crystalline Form II 2-(3) for use in the treatment of pruritus associated with allergic dermatitis in non-human mammals. -(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile. A preferred non-human mammal is a dog. In certain embodiments, the dog is at least 9 months old or at least 12 months old.

In certain embodiments, the present disclosure relates to dermatological conditions in non-human mammals [e.g., skin disorders such as psoriasis (e.g., psoriasis vulgaris), atopic dermatitis, rashes, skin irritation, skin sensitization (e.g., 2-(3-( Use of 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile or a salt thereof is provided do. A preferred non-human mammal is a dog. In certain embodiments, the dog is at least 9 months old or at least 12 months old.

In preferred embodiments, the present disclosure is directed to dermatological conditions [e.g., skin disorders such as psoriasis (e.g., psoriasis vulgaris), atopic dermatitis, rashes, skin irritation, skin sensitization (e.g. Contact dermatitis or allergic contact dermatitis), itching and allergic reactions, including itching associated with allergic dermatitis], or Form II for the manufacture of a medicament for the treatment of , or Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidine-3- yl) provide the use of acetonitrile. A preferred non-human mammal is a dog. In certain embodiments, the dog is at least 9 months old or at least 12 months old.

In particularly preferred embodiments, the present disclosure is directed to dermatological conditions [e.g., skin disorders such as psoriasis (e.g., psoriasis vulgaris), atopic dermatitis, rashes, skin irritation, skin sensitization (e.g., , contact dermatitis or allergic contact dermatitis), itching and allergic reactions, including itching associated with allergic dermatitis], for the manufacture of a medicament for the treatment of crystalline form II 2- ( Use of 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile is provided do. A preferred non-human mammal is a dog. In certain embodiments, the dog is at least 9 months old or at least 12 months old.

In a further particularly preferred embodiment, the present disclosure is directed to dermatological conditions [e.g., skin disorders such as psoriasis (e.g., psoriasis vulgaris), atopic dermatitis, rashes, skin irritation, skin sensitization ( contact dermatitis or allergic contact dermatitis), itching and allergic reactions, including itching associated with allergic dermatitis, etc.] 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidine -3-yl)acetonitrile. A preferred non-human mammal is a dog. In certain embodiments, the dog is at least 9 months old or at least 12 months old.

In certain embodiments, the present disclosure provides 2-(3-(4-(7H-pyrrolo[2,3-d]) for the manufacture of a medicament for the treatment of atopic dermatitis in a non-human mammal. Use of pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile or a salt thereof is provided. In a preferred embodiment, the present disclosure provides crystalline Form I, or Form II, or Form III 2-(3-(4-( Use of 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile is provided. In a particularly preferred embodiment, the present disclosure provides crystalline Form II 2-(3-(4-(7H-pyrrolo[2,3 -d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile. In a more particularly preferred embodiment, the present disclosure provides substantially polymorphically pure crystalline Form II 2-(3-() for the manufacture of a medicament for the treatment of atopic dermatitis in non-human mammals. Use of 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile is provided. A preferred non-human mammal is a dog. In certain embodiments, the dog is at least 9 months old or at least 12 months old.

In certain embodiments, the present disclosure provides 2-(3-(4-(7H-pyrrolo[2 ,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile or a salt thereof. In a preferred embodiment, the present disclosure provides crystalline Form I, or Form II, or Form III 2-(3) for the manufacture of a medicament for the treatment of pruritus associated with allergic dermatitis in non-human mammals. -(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile . In a particularly preferred embodiment, the present disclosure provides crystalline Form II 2-(3-(4-(7H-) for the manufacture of a medicament for the treatment of pruritus associated with allergic dermatitis in non-human mammals. Use of pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile is provided. In a more particularly preferred embodiment, the present disclosure provides substantially polymorphically pure crystalline Form II 2 for the manufacture of a medicament for the treatment of pruritus associated with allergic dermatitis in non-human mammals. Use of -(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile I will provide a. A preferred non-human mammal is a dog. In certain embodiments, the dog is at least 9 months old or at least 12 months old.

The following examples are offered to illustrate the invention and are not intended to be limiting in any way.

Example 1
2-[1-cyclopropylsulfonyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]azetidin-3-yl] Acetonitrile 2-(1-Cyclopropylsulfonylazetidin-3-ylidene)acetonitrile (850 g) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- Pyrazole (874 g) was combined in acetonitrile (2.6 L). 1,8-Diazabicyclo[5.4.0]undec-7-ene (65g) was added and the mixture was heated to 70°C. After 2.5 hours, the reaction mixture was cooled to ambient temperature over about 2 hours. Water (5.2 L) was slowly added to the mixture over about 1 hour and the mixture was stirred for about 3 hours. The solid that forms is collected by filtration and dried under vacuum at 45° C. for about 24 hours to give 2-[1-cyclopropylsulfonyl-3-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrazol-1-yl]azetidin-3-yl]acetonitrile.

Example 2
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile phosphorus Potassium acid (829 g) was combined with water (1 L) and cooled to ambient temperature. THF (2 L) was added. 4-Chloropyrrolo[2,3-d]pyrimidine (200 g) was added followed by di-tert-butyl dicarbonate (344 g). The reaction mixture was stirred at ambient temperature for 24 hours. The reaction mixture was sparged with nitrogen gas for 60 minutes. 2-[1-cyclopropylsulfonyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]azetidin-3-yl] Acetonitrile (562 g) and Pd-134 (6.6 g) were added and the reaction temperature was raised to 60°C. After about 2 hours, the aqueous layer was separated, silica thiol (40 g) was added and the reaction was stirred at 60° C. for 18 hours. The reaction mixture was filtered at 60°C, then the filtrate was cooled to 10-20°C with stirring to give a solid, which was collected by filtration, rinsed with cold THF, and then filtered at 40-50°C for 2 minutes. Dried under vacuum for an hour to give tert-butyl 4-[1-[3-(cyanomethyl)-1-cyclopropylsulfonyl-azetidin-3-yl]pyrazol-4-yl]pyrrolo[2,3-d]pyrimidine -7-carboxylate (540 g) was obtained.

tert-butyl 4-[1-[3-(cyanomethyl)-1-cyclopropylsulfonyl-azetidin-3-yl]pyrazol-4-yl]pyrrolo[2,3-d]pyrimidine-7-carboxy obtained above Rat (540 g) was combined with n-butanol (3 L) and water (770 mL) and heated to 90°C. After 6 hours, the reaction was cooled to 80° C. within 30 minutes, then stirred at 80° C. for 30 minutes, then cooled to 20° C. over 6 hours, stirred at 10-20° C. for 16 hours, solid which was filtered to give 460 g of the title compound (as wet cake).

Example 3
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile phosphorus Potassium acid (829 g) was combined with water (1 L) and cooled to ambient temperature. THF (2 L) was added. 4-Chloropyrrolo[2,3-d]pyrimidine (200 g) was added followed by di-tert-butyl dicarbonate (344 g). The reaction mixture was stirred at ambient temperature for 24 hours. The reaction mixture was sparged with nitrogen gas for 60 minutes. 2-[1-cyclopropylsulfonyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]azetidin-3-yl] Acetonitrile (562 g) and Pd-134 (6.6 g) were added and the reaction temperature was raised to 60°C. After about 2 hours, the aqueous layer was separated, silica thiol (40 g) was added and the reaction was stirred at 60° C. for 18 hours. The reaction mixture is filtered at 60°C, then the filtrate is cooled to 10-20°C with stirring to give a solid, which is collected by filtration, rinsed with cold THF, then 40-50°C. tert-butyl 4-[1-[3-(cyanomethyl)-1-cyclopropylsulfonyl-azetidin-3-yl]pyrazol-4-yl]pyrrolo[2,3-d ] pyrimidine-7-carboxylate (525 g) was obtained.

tert-butyl 4-[1-[3-(cyanomethyl)-1-cyclopropylsulfonyl-azetidin-3-yl]pyrazol-4-yl]pyrrolo[2,3-d]pyrimidine-7-carboxy obtained above Rat (540 g) was combined with n-butanol (3 L) and water (770 mL) and heated to 90°C. After 6 hours, the reaction was cooled to 80° C. within 30 minutes, then stirred at 80° C. for 30 minutes, then cooled to 20° C. over 6 hours, stirred at 10-20° C. for 16 hours, solids , which was filtered to give 454 g of the title compound (as wet cake).

Example 4
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form II
The wet cakes (approximately 907 g) from Examples 2 and 3 were combined in acetonitrile (4 L) and stirred at 60° C. for 2 hours. The reaction mixture was cooled to 20° C. over 6 hours and then stirred at 20° C. for 12 hours. The solid was collected by filtration, rinsed with acetonitrile and dried under vacuum at 50-60° C. for 24 hours to give the title compound (695 g).

Example 5
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form I
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile ( 104.1 mg) was combined with acetone (8 mL) and heated to 55°C. After 30 minutes, the reaction mixture was cooled at a rate of 0.02°C/min to a temperature of 30°C, then at a rate of 0.1°C/min to a temperature of 5°C, during which time 2.94 mL/h Simultaneous addition of heptane (12 mL) at a rate of , gave a solid that was collected by filtration and dried to give the title compound (79.5 mg).

Example 6
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form II
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile ( 152.4 mg) was combined with acetonitrile (8.1 mL) and heated to 80°C. After 30 minutes, the reaction mixture was cooled at a rate of 0.05°C/min to a temperature of 5°C to give a solid which was collected by filtration and dried to give the title compound (93.4mg). .

Example 7
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form II
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile ( 157.8 mg) was combined with acetonitrile/water 96:4 (v/v) (4.2 mL) and heated to 80°C. After 30 minutes, the reaction mixture was cooled at a rate of 0.05°C/min to a temperature of 5°C to give a solid which was collected by filtration and dried to give the title compound (89.4mg). .

Example 8
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form II
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile ( 5g) was combined with acetonitrile/water 96:4 (v/v) (100 mL) and heated to 80°C. After about 75 minutes, the reaction mixture was cooled at a rate of 0.20°C/min to a temperature of 70°C, then seed crystals (2 x 0.25g) were added and 8 Cooling was continued to a temperature of °C to obtain a solid. After about 6 hours, the solid was collected by filtration and dried to give the title compound (4.88g).

Example 9
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form II
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile ( 20.6 mg) was combined with 4:1 (v/v) methanol/water (0.3 mL) having a water activity of about 0.5 and stirred at 25° C. for 4 days and a further 4:1 (v/v ) methanol/water (0.5 mL) was added and stirring was continued at 25° C. for 6 days, then solids were collected by filtration centrifugation (3 min, 5000 rpm, 0.2 μm PVDF membrane) to give the title compound. Obtained.

Example 10
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form II
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile ( 10 g) was combined with acetonitrile/water 96:4 (v/v) (250 mL) and heated to 72°C. After about 60 minutes, the reaction mixture was cooled at a rate of 0.20°C/min to a temperature of 65°C, then seeds (0.10 g) were added and the temperature was cooled to 35°C at a rate of 0.035°C/min. to obtain a solid, then cooled to a temperature of 5°C at a rate of 0.125°C/min to obtain a solid. After about 3 hours, the solid was collected by filtration and dried to give the title compound (8.51g).

Example 11
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form II
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile ( 70.3 mg) was combined with 0.2 mL of 9:1 (v/v) acetone/water and heated to 60° C. with stirring. Additional 9:1 (v/v) acetone/water was added slowly, totaling about 1.6 mL. The temperature was held at 60°C for 1.5 hours, then the mixture was cooled to 10°C at a rate of 0.05°C/min and held at 10°C for 2 hours and 45 minutes to give a solid. The solid was collected by filter centrifugation (2 minutes, 5000 rpm) to give the title compound.

Example 12
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form II
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile ( 149.8 mg) was combined with acetonitrile (8.0 mL) and heated to 80°C. After 30 minutes, the reaction mixture was cooled to a temperature of 55°C at a rate of 0.02°C/min. The reaction mixture was then cooled at a rate of 0.1° C./min over the range of 55° C. to 5° C. while simultaneously cooling the entire mixture at a rate of 1.44 mL/h over the same duration as the cooling ramp from 55° C. to 5° C. 12 mL of isopropyl acetate was added at rt to give a solid that was collected by filtration and dried to give the title compound (94.2 mg).

Example 13
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form II
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile ( 208.5 mg) was combined with 0.2 mL of 3:1 (v/v) methanol/water and heated to 60° C. with stirring. Additional 3:1 (v/v) methanol/water was added slowly, totaling about 23.2 mL. The temperature was held at 60° C. for 30 minutes, then the mixture was cooled to 10° C. at a rate of 0.05° C./min and held at 10° C. for 20 minutes to obtain a solid. The solid was collected by filtration to give the title compound.

Example 14
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form III
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile ( 60 mg) is combined with 2 mL of 5:1 (v/v) 1-butanol/water with a water activity of approximately 0.9 and stirred at room temperature for 10 days, followed by filtration centrifugation (2 min, 5000 rpm, 0.9 min). The solid was collected by a 2 μm PTFE membrane) to give the title compound.

Example 15
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form III
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile ( 33 mg) is combined with 0.4 mL of 3:2 (v/v) methanol/water with a water activity of about 0.7 and stirred at about 20° C. for 14 days, followed by filtration centrifugation (2 minutes, 4400 rpm, The solid was collected by a 0.2 μm PTFE membrane) to give the title compound.

Example 16
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form II
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile ( 60.4 mg) was combined with acteophenone (1 mL) and stirred at room temperature for 10 days, then the solid was collected by filtration centrifugation (2 min, 5000 rpm, 0.2 μm PTFE membrane) to give the title compound.

Example 17
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form II
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile ( 59.9 mg) was combined with butyronitrile (2 mL) and stirred at room temperature for 10 days, then the solid was collected by filtration centrifugation (2 min, 5000 rpm, 0.2 μm PTFE membrane) to give the title compound.

Example 18
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form II
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile ( 60.3 mg) was combined with cyclohexanone (1.5 mL) and stirred at room temperature for 10 days, then the solid was collected by filtration centrifugation (2 min, 5000 rpm, 0.2 μm PTFE membrane) to give the title compound.

Example 19
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form II
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile ( 60.9 mg) was combined with dioxane (2 mL) and stirred at room temperature for 10 days, then the solid was collected by filtration centrifugation (2 min, 5000 rpm, 0.2 μm PTFE membrane) to give the title compound.

Example 20
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form II
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile ( 60.0 mg) was combined with ethyl formate (1.5 mL) and stirred at room temperature for 10 days, then solids were collected by filtration centrifugation (2 min, 5000 rpm, 0.2 μm PTFE membrane) to give the title compound. .

Example 21
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form II
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile ( 59.4 mg) was combined with methyl acetate (1.5 mL) and stirred at room temperature for 10 days, then solids were collected by filtration centrifugation (2 min, 5000 rpm, 0.2 μm PTFE membrane) to give the title compound. .

Example 22
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form II
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile ( 60.5 mg) was combined with nitrobenzene (2 mL) and stirred at room temperature for 10 days, then the solid was collected by filtration centrifugation (2 min, 5000 rpm, 0.2 μm PTFE membrane) to give the title compound.

Example 23
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form II
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile ( 60.5 mg) was combined with anisole (0.6 mL) and stirred at 40° C. for 6 days, then solids were collected by filtration centrifugation (2 min, 5000 rpm, 0.2 μm PTFE membrane) to give the title compound. .

Example 24
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form II
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile ( 59.8 mg) was combined with ethyl formate (0.6 mL) and stirred at 40° C. for 6 days, then solids were collected by filtration centrifugation (2 min, 5000 rpm, 0.22 μm PVDF membrane) to give the title compound. rice field.

Example 25
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form II
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile ( 60.5 mg) was combined with isopropyl acetate (0.6 mL) and stirred at 40° C. for 6 days, then solids were collected by filtration centrifugation (2 min, 5000 rpm, 0.22 μm PVDF membrane) to give the title compound. rice field.

Example 26
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form II
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile ( 60.4 mg) was combined with isopentanol (1 mL) and stirred at 40° C. for 6 days, then the solid was collected by filtration centrifugation (2 min, 5000 rpm, 0.2 μm PTFE membrane) to give the title compound. .

Example 27
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form II
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile ( 60.4 mg) was combined with methyl isobutyl ketone (1 mL) and stirred at 40° C. for 6 days, then solids were collected by filtration centrifugation (2 minutes, 5000 rpm, 0.22 μm PTFE membrane) to give the title compound. .

Example 28
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form II
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile ( 60.6 mg) is combined with 3:1 (v/v) ethanol/water (0.9 mL) having a water activity of about 0.7 and stirred at 40° C. for 6 days, followed by filtration centrifugation (2 min, 5000 rpm, 0.22 μm PVDF membrane) to collect the solid to give the title compound.

Example 29
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form II
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile ( 69.7 mg) was combined with 1-propanol (10.8 mL) and heated to 60° C. with stirring. Dimethylsulfoxide (2 mL) was slowly added to an approximately 85:15 (v/v) mixture of 1-propanol/DMSO. The temperature was held at 60° C. for about 1.5 hours, then the mixture was cooled to 10° C. at a rate of 0.05° C./min and held at 10° C. for 7.5 hours, then 1-propanol (5 mL) was added. Addition and then the mixture was stirred at 5° C. for 10 days to give a solid which was collected by filtration to give the title compound.

Example 30
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form III
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile ( 70.6 mg) was combined with ethyl acetate saturated with water (0.2 mL) and heated to 60° C. with stirring, then ethyl acetate (7.2 mL) was added and the mixture was stirred at 60° C. for ca. Stir for an hour, then cool the mixture to 10° C. at a rate of 0.05° C./min, then collect the solid by filtration centrifugation (2 min, 5000 rpm, 0.2 μm PTFE membrane) to give the title compound. rice field.

Example 31
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form III
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile ( 199.6 mg) was combined with ethyl acetate saturated with water (2.0 mL) and stirred at room temperature for 2 days, then solids were collected by filtration centrifugation (2 min, 5000 rpm, 0.2 μm PTFE membrane). , to give the title compound.

Example 32
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form I
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole- 1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile Form III was obtained to give the title compound.

Example 33
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form II
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile ( 60.3 mg) was combined with ethanol (1 mL) and stirred at 5° C. for 7 days, then the solid was collected by filtration centrifugation (2 minutes, 5000 rpm, 0.45 μm PVDF membrane) to give the title compound.

Example 34
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form II
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile ( 60.4 mg) was combined with methanol (1 mL) and stirred at 5° C. for 7 days, then the solid was collected by filtration centrifugation (2 min, 5000 rpm, 0.45 μm PVDF membrane) to give the title compound.

Example 35
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form II
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile ( 60.0 mg) was combined with isopropanol (1 mL) and stirred at 5° C. for 7 days, then the solid was collected by filtration centrifugation (2 min, 5000 rpm, 0.45 μm PVDF membrane) to give the title compound.

Example 36
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form II
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile ( 60.3 mg) was combined with 1-butanol (2 mL) and stirred at 5° C. for 7 days, then solids were collected by filtration centrifugation (2 min, 5000 rpm, 0.45 μm PVDF membrane) to give the title compound. .

Example 37
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form II
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile ( 59.6 mg) was combined with ethanol (1 mL) and stirred at 60° C. for 5 days, then the solid was collected by filtration centrifugation (2 minutes, 5000 rpm, 0.45 μm PVDF membrane) to give the title compound.

Example 38
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form II
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile ( 59.9 mg) was combined with methanol (1 mL) and stirred at 60° C. for 5 days, then the solid was collected by filtration centrifugation (2 minutes, 5000 rpm, 0.45 μm PVDF membrane) to give the title compound.

Example 39
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form II
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile ( 60.1 mg) was combined with isopropanol (1.5 mL) and stirred at 60° C. for 5 days, then the solid was collected by filtration centrifugation (2 min, 5000 rpm, 0.45 μm PVDF membrane) to give the title compound. .

Example 40
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form II
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile ( 60.6 mg) was combined with 1-butanol (1.5 mL) and stirred at 60° C. for 5 days, then solids were collected by filtration centrifugation (2 minutes, 5000 rpm, 0.45 μm PVDF membrane) to give the title compound. Obtained.

Example 41
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form II
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile ( 10.4 mg) was combined with acetonitrile (0.5 mL) and stirred at 20° C. for 1 day, then solids were collected by filtration centrifugation (1 min, 4500 g rcf, 0.2 μm PTFE membrane) to give the title compound. rice field.

Example 42
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form II
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile ( 10.3 mg) was combined with acetone (0.5 mL) and stirred at 20° C. for 1 day, then solids were collected by filtration centrifugation (2 min, 4000 g rcf, 0.2 μm PTFE membrane) to give the title compound. rice field.

Example 43
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form II
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile ( 20.6 mg) are combined with 4:1 (v/v) methanol/water (0.4 mL) having a water activity of about 0.5 and stirred at 25° C. for 4 days, then a further 4:1 (v/ v) Methanol/water (0.5 mL) was added and stirred at 25° C. for 6 days, then the solid was collected by filtration centrifugation (3 min, 5000 rpm, 0.2 μm PVDF membrane) to give the title compound .

Example 44
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form II
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile ( 539.9 mg) was combined with 1:1 (v/v) ethanol/acetone (18 mL) and stirred at 60° C. for 45 min, then cooled at a rate of 0.05° C./min to a temperature of 5° C., solid which was collected by filtration and dried under vacuum at 40° C. to give the title compound.

Example 45
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form II
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile ( 256.1 mg) was combined with 7:3 (v/v) acetone/isopropyl acetate (13.5 mL) and stirred at 60° C. for 1 hour, then cooled to a temperature of 5° C. at a rate of 0.02° C./min. to give a solid which was collected by filtration and dried under vacuum at 40° C. to give the title compound.

Example 46
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form III
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile ( 60 mg) is combined with 5:1 (v/v) 1-butanol/water (2 mL) having a water activity of about 0.9 and stirred at room temperature for 10 days, followed by filtration centrifugation (2 min, 5000 rpm, 0 The solid was collected by a .2 μm PTFE membrane) to give the title compound.

Example 47
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile form III
2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile ( 60.1 mg) is combined with 1:1 (v/v) acetonitrile/water (0.9 mL) having a water activity of about 0.9 and stirred at 40° C. for 6 days, followed by filtration centrifugation (2 min, 5000 rpm, 0.2 μm PTFE membrane) to collect the solid to give the title compound.

Example 48
Control of Pruritus and Skin Lesions Associated with Allergic Dermatitis in Dogs [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile was evaluated.

Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidine as follows -3-yl)acetonitrile was prepared. Crystal Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl ) An oral tablet blend containing acetonitrile, microcrystalline cellulose, pregelatinized starch, dicalcium phosphate dehydrate, oxide pigment and magnesium stearate was prepared. The tablet blend is compressed to give 2.4 mg, 3.6 mg, 5.4 mg and 16 mg of crystalline Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl) A tablet core containing -1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile as well as a placebo core were obtained. The tablet cores were coated with a mixture containing water and Opadry 20A150011 Red to obtain the final oral tablets for testing.

2-(3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole-1-for control of pruritus and skin lesions associated with allergic dermatitis in dogs A four-arm, blinded, randomized, placebo-controlled study was conducted to evaluate the efficacy of daily administration of yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile. Subjects were randomized to one of the following treatment groups: API-containing tablets, 0.25-0.40 mg/kg body weight; API-containing tablets, 0.40-0.60 mg/kg body weight; 0.60-0.80 mg/kg body weight; and placebo tablet, 0.0 mg/kg body weight.

Dogs enrolled in this study received treatment once daily for approximately 28 days. Baseline data (clinical history, concomitant medications, body weight, physical examination and assessment of pruritus and atopic dermatitis) were collected for each dog at enrollment (Day 0). Further health evaluation, physical examination, weight measurements, assessment of pruritus and atopic dermatitis, and collection of blood samples for hematology, serum chemistry and pharmacokinetic (PK) analysis were performed in accordance with standard study protocols. rice field.

The primary efficacy variable was response to treatment. Treatment response was 2 units from baseline on a 10-unit self-rated pruritus visual analog scale (VAS) on at least 70% of the first 7 treatment days (i.e., at least 5 of the first 7 treatment days). defined as a decrease in Dogs that discontinued the study within the first 7 days of treatment due to lack of perceived efficacy were considered treatment failures. The minimal effective dose was defined in the protocol as the dose at which treatment response was achieved in at least 50% of dogs.

Table 2 shows 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidine-3- yl) acetonitrile (0.60-0.80 mg/kg) was statistically significantly higher than the placebo response rate of 0.2935 (95% confidence interval 0.1571, 0.4808) at 0.7188 It has a response rate of (95% confidence limits 0.5331, 0.8512); indicating a p-value for comparison (on the logit scale) of 0.0006. Thus, the highest dose group (0.6-0.8 mg/kg) achieved the primary endpoint for treatment response. In addition, once daily dosing at 0.6-0.8 mg/kg showed significant improvement in pruritus from the first dose and this group showed significant improvement in lesion scores on day 28 of the study. Indicated. Estimated marginal mean response rates for low (0.24-0.4 mg/kg) and medium (0.4-0.6 mg/kg) doses were also higher than placebo rates. The results are based on a general linear mixed model with fixed-effect terms for treatment and Day 0 VAS scores. Variance component covariance structures were used to fit random effects to site and site treatment, and compound symmetric covariance structures were fit to individual dogs.

8. Representative Embodiments For completeness, various aspects of the disclosure are presented in the following numbered sections.

Article 1.12.72° (43.1%), 14.04° (61.3%), 17.56° (20.8%), 20.33° (87.4%), 24.50 A substantially polymorphically pure crystalline characterized by an X-ray powder diffraction pattern containing peaks at ° (100%) and 25.83° (94.9%) (±0.2° 2-theta) 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile.

Clause 2. Substantially polymorphically pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl) according to clause 1 - A pharmaceutical composition comprising 1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile and a pharmaceutically acceptable excipient.

Article 3. Substantially polymorphically pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl) according to clause 1 - A process for making 1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile comprising crystallization from acetone and heptane.

Article 4. Substantially polymorphically pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl) according to clause 1 A process for making 1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile comprising 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl) -1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile.

Article 5. A method of treating a dermatological condition comprising administering to a non-human mammal in need thereof substantially polymorphically pure crystalline 2-(3-(4-(7H-) according to clause 1. A method comprising administering an effective amount of pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile.

Clause 6. 6. The method of clause 5, wherein the dermatological condition is selected from the group consisting of atopic dermatitis and pruritus.

Article 7. 7. The method of clause 6, wherein the non-human mammal is a dog.

Article 8.5.34°, 10.68°, 14.26°, 16.06°, 16.39°, 16.48°, 18.26°, 18.65°, 21.05°, 21. Substantially polymorphically pure crystalline 2-(3 -(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile.

Clause 9. Substantially polymorphically pure crystalline 2-(3 -(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile.

Clause 10. Substantially polymorphically pure crystalline 2-(3 -(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile.

Clause 11. A substantially polymorphically pure crystalline 2-(3 -(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile.

Clause 12. Substantially polymorphically pure crystalline 2-(3 -(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile.

Article 13. Substantially polymorphically pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H according to any one of clauses 8-12 - a pharmaceutical composition comprising pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile and a pharmaceutically acceptable excipient.

Article 14. Substantially polymorphically pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H according to any one of clauses 8-12 -pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile, each having a water activity of less than about 0.7 C _1-5 alcohols, C Crystallizing from a solvent or mixture of solvents selected from the group consisting of _2-8 alkyl ethers, C _2-8 alkyl acetates, C _2-5 alkyl cyanides, C _3-9 alkyl ketones and aromatic solvents. process.

Article 15. Substantially polymorphically pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H according to any one of clauses 8-12 -pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile, each having a water activity of less than about 0.5 C _1-5 alcohols, C Crystallizing from a solvent or mixture of solvents selected from the group consisting of _2-8 alkyl ethers, C _2-8 alkyl acetates, C _2-5 alkyl cyanides, C _3-9 alkyl ketones and aromatic solvents. process.

Article 16. Substantially polymorphically pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H according to any one of clauses 8-12 - A process of making pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile comprising crystallization from acetonitrile having a water activity of less than 0.7.

Article 17. Substantially polymorphically pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H according to any one of clauses 8-12 - A process of making pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile comprising crystallization from acetonitrile having a water activity of less than 0.5.

Article 18. A method of treating a dermatological condition comprising administering to a non-human mammal in need thereof a crystalline 2-(3-(4-(7H-pyrrolo[ 2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile.

Article 19. 19. The method of clause 18, wherein the dermatological condition is selected from the group consisting of atopic dermatitis and pruritus.

Clause 20. 20. The method of clause 19, wherein the non-human mammal is a dog.

Clause 21.11.08°, 14.73°, 18.06°, 18.27°, 18.51°, 22.24°, 22.69°, 24.76°, 25.48° or 28. Substantially polymorphically pure crystalline 2-(3-(4-(7H-pyrrolo[2 ,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile.

Clause 22. Substantially polymorphically pure crystalline 2-(3 -(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile.

Substantially polymorphically pure crystalline 2-(3) characterized by an X-ray powder diffraction pattern containing peaks at clauses 23.14. -(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile.

Substantially polymorphically pure crystalline 2-(3 -(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile.

Clause 25. Substantially polymorphically pure crystalline 2-(3 -(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile.

Substantially polymorphically pure crystalline 2-(3 -(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile.

Article 27. Substantially polymorphically pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H according to any one of clauses 21-26 - a pharmaceutical composition comprising pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile and a pharmaceutically acceptable excipient.

Article 28. Substantially polymorphically pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H according to any one of clauses 21-26 -pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile, C _1-5 alcohols, each having a water activity greater than about 0.9 A process comprising crystallization from a solvent or mixture of solvents selected from the group consisting of _2-8 alkyl ethers, C _2-8 alkyl acetates, C _2-5 alkyl cyanides and C _3-9 alkyl ketones.

Article 29. Substantially polymorphically pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H according to any one of clauses 21-26 -pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile, the group consisting of C _1-5 alcohols having a water activity greater than about 0.9 A process comprising crystallization from a solvent or mixture of solvents selected from

Clause 30. A method of treating a dermatological condition comprising administering to a non-human mammal in need thereof a crystalline 2-(3-(4-(7H-pyrrolo[ 2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile.

Article 31. Clause 31. The method of clause 30, wherein the dermatological condition is selected from the group consisting of atopic dermatitis and pruritus.

Article 32. 32. The method of clause 31, wherein the non-human mammal is a dog.

Clauses 33.5.34°, 10.68°, 14.26°, 16.06°, 16.39°, 16.48°, 18.26°, 18.65°, 21.05°, 21. Substantially polymorphically pure crystalline 2-(3 -(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile.

Clause 34. A substantially polymorphically pure crystal according to Clause 33, characterized by an X-ray powder diffraction pattern comprising peaks at 18.65° and 10.68° (±0.2° 2-theta). 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile .

Clause 35. A substantially polymorphically pure crystal according to Clause 33, characterized by an X-ray powder diffraction pattern comprising peaks at 18.65° and 21.76° (±0.2° 2-theta). 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile .

Clause 36. A substantially polymorphically pure crystal according to Clause 33, characterized by an X-ray powder diffraction pattern comprising peaks at 18.65° and 22.68° (±0.2° 2-theta). 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile .

Clause 37. A substantially polymorphically pure crystal according to Clause 33, characterized by an X-ray powder diffraction pattern comprising peaks at 26.75° and 21.76° (±0.2° 2-theta). 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile .

Article 38. Substantially polymorphically pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H according to any one of clauses 33-37 - a pharmaceutical composition comprising pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile and a pharmaceutically acceptable excipient.

Article 39. Substantially polymorphically pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H according to any one of clauses 33-37 -pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile, each having a water activity of less than about 0.7 C _1-5 alcohols, C Crystallizing from a solvent or mixture of solvents selected from the group consisting of _2-8 alkyl ethers, C _2-8 alkyl acetates, C _2-5 alkyl cyanides, C _3-9 alkyl ketones and aromatic solvents. process.

Clause 40. Substantially polymorphically pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H according to any one of clauses 33-37 -pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile, each having a water activity of less than about 0.5 C _1-5 alcohols, C Crystallizing from a solvent or mixture of solvents selected from the group consisting of _2-8 alkyl ethers, C _2-8 alkyl acetates, C _2-5 alkyl cyanides, C _3-9 alkyl ketones and aromatic solvents. process.

Article 41. Substantially polymorphically pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H according to any one of clauses 33-37 - A process of making pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile comprising crystallization from acetonitrile having a water activity of less than 0.7.

Article 42. Substantially polymorphically pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H according to any one of clauses 33-37 - A process of making pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile comprising crystallization from acetonitrile having a water activity of less than 0.5.

Article 43. A method of treating a dermatological condition comprising administering to a non-human mammal in need thereof 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H -pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile or a salt thereof.

Article 44. A method of controlling pruritus associated with allergic dermatitis and controlling atopic dermatitis comprising administering to a non-human mammal in need thereof 2-(3-(4-(7H-pyrrolo[2, 3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile or a salt thereof.

Article 45. 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4) in a non-human mammal in need thereof. -yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile or a salt thereof.

Article 46. A method of treatment of clinical symptoms of atopic dermatitis comprising administering to a non-human mammal in need thereof 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl) )-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile or a salt thereof.

Article 47. 47. The method of any one of clauses 43-46, wherein the non-human mammal is a dog.

Article 48. 48. The method of clause 47, wherein the dog is at least 12 months old.

Article 49. 49. The method of any one of clauses 43-48, wherein the effective amount is 0.6-0.8 mg/kg.

Clause 50. 49. The method of any one of clauses 43-49, wherein administration to the non-human mammal is once daily.

Clause 51.2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl ) The method of any one of clauses 43-50, wherein the acetonitrile is crystalline.

Clause 52.2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl ) The method of any one of clauses 43-51, wherein the acetonitrile is in crystalline form I, crystalline form II, crystalline form III or any combination thereof.

Clause 53.2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl ) acetonitrile at 5.34°, 10.68°, 14.26°, 16.06°, 16.39°, 16.48°, 18.26°, 18.65°, 21.05°, 21 Substantially polymorphically pure crystalline 2-( 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile 52. The method of any one of 43-51.

Clause 54.2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl ) acetonitrile is substantially polymorphically pure crystalline 2-( 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile 52. The method of any one of 43-51.

Clause 55. 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl ) acetonitrile is substantially polymorphically pure crystalline 2-( 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile 52. The method of any one of 43-51.

Clause 56.2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl ) acetonitrile is substantially polymorphically pure crystalline 2-( 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile 52. The method of any one of 43-51.

Clause 57.2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl ) acetonitrile is substantially polymorphically pure crystalline 2-( 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile 52. The method of any one of 43-51.

Clause 58.2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl ) oral dosage forms containing acetonitrile or its salts.

Clause 59.2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl ) oral dosage forms containing acetonitrile.

Article 60. Crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl) An oral dosage form containing acetonitrile.

Clause 61.2.4 mg, 3.6 mg, 4.8 mg, 5.4 mg, 6.4 mg, 8.5 mg, 15 mg or 16 mg of 2-(3-(4-(7H-pyrrolo[2,3-d] An oral dosage form comprising pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile.

Clause 62.2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl ) acetonitrile is 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidine-3- yl) An oral dosage form according to any one of clauses 58-61 which is acetonitrile Form I, Form II or Form III or a combination thereof.

Clause 63.2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl ) acetonitrile at 5.34°, 10.68°, 14.26°, 16.06°, 16.39°, 16.48°, 18.26°, 18.65°, 21.05°, 21 Substantially polymorphically pure crystalline 2-( 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile An oral dosage form according to any one of paragraphs 58-62.

Article 64. 64. Oral according to any one of clauses 58-63, wherein the oral dosage form further comprises microcrystalline cellulose, pregelatinized starch, dicalcium phosphate dehydrate, oxide pigments or magnesium stearate or any combination thereof. dosage form.

Claims (13)

5.34°, 10.68°, 14.26°, 16.06°, 16.39°, 16.48°, 18.26°, 18.65°, 21.05°, 21.76°, Substantially polymorphically pure crystalline 2-(3-(4 -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile. are selected from the group consisting of C _1-5 alcohols, C _2-8 alkyl ethers, C _2-8 alkyl acetates, C _2-5 alkyl cyanides, C _3-9 alkyl ketones and aromatic solvents or mixtures thereof wherein said solvent or mixture of solvents has a water activity of less than 0.7. said substantially polymorphically pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-( Claim 1, wherein the cyclopropylsulfonyl)azetidin-3-yl)acetonitrile is characterized by an X-ray powder diffraction pattern comprising peaks at 18.65° and 10.68° (±0.2° 2θ). process. said substantially polymorphically pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-( Claim 1, wherein the cyclopropylsulfonyl)azetidin-3-yl)acetonitrile is characterized by an X-ray powder diffraction pattern comprising peaks at 18.65° and 21.76° (±0.2° 2θ). process. said substantially polymorphically pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-( Claim 1, wherein the cyclopropylsulfonyl)azetidin-3-yl)acetonitrile is characterized by an X-ray powder diffraction pattern comprising peaks at 18.65° and 22.68° (±0.2° 2θ). process. said substantially polymorphically pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-( Claim 1, wherein the cyclopropylsulfonyl)azetidin-3-yl)acetonitrile is characterized by an X-ray powder diffraction pattern comprising peaks at 26.75° and 21.76° (±0.2° 2θ). process. The process of any one of claims 1-5, wherein the solvent or mixture of solvents has a water activity of less than about 0.5. A process according to any one of claims 1 to 5, wherein said crystallization is from acetonitrile with a water activity of less than 0.7. A process according to any one of claims 1 to 5, wherein said crystallization is from acetonitrile with a water activity of less than 0.5. The process of any one of claims 1-8, wherein the solvent comprises acetonitrile. 10. The process of claim 9, wherein the v/v ratio of acetonitrile and water is 92-97 acetonitrile to 8-3 water. 10. The process of claim 9, wherein the v/v ratio of acetonitrile and water is 95-97 acetonitrile to 5-3 water. 10. The process of claim 9, wherein the v/v ratio of acetonitrile and water is about 96 acetonitrile to 4 water. said substantially polymorphically pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-( Cyclopropylsulfonyl)azetidin-3-yl)acetonitrile is 5.34°, 10.68°, 14.26°, 16.06°, 16.39°, 16.48°, 18.26°, 18. characterized by an X-ray powder diffraction pattern comprising peaks at 65°, 21.05°, 21.76°, 22.68° and 26.75° (±0.2° 2-theta) A process according to any one of paragraphs.